The present invention is related to methods for providing local anesthesia with greatly enhanced safety and reduced risk of toxicity. In particular, methods are provided for increasing the safety and reducing the risk of toxic reactions and side effects by the use of biocompatible, biodegradable, controlled release formulations for the administration of local anesthetics in a form that provides greatly enhanced safety.
Local anesthetics act to produce a loss of sensation and/or motor function in the localized area of administration in the body. Ideally, a local anesthetic does not cause local tissue irritation and does not cause permanent damage to the nerve tissue to which it is applied, i.e., the local anesthesia should be non-toxic and reversible. It is also desirable for a local anesthetic to have low systemic toxicity, since these agents are ultimately absorbed systemically, where sufficient blood and/or tissue levels can cause cardiac toxicity. Further, there is the possibility that such agents could accidentally be injected into a blood vessel or ingested, greatly increasing the risk of untoward effects.
The art has recognized the need for compositions and methods for providing safe local anesthesia with rapid onset and a reasonably prolonged duration, e.g., up to eight hours of local anesthesia. However, methods and formulations heretofore available for providing local anesthesia, particularly local anesthesia lasting as long as eight hours, place the patient at risk for local and systemic toxic effects, such as an increased risk of neurolysis and tissue necrosis and systemic toxicity due to redistribution of excess locally administered local anesthetic into the general circulation.
The duration of action of a local anesthetic is proportional to the time during which it is in actual contact with the nervous tissues. Consequently, procedures or formulations that maintain localization of the drug at the nerve greatly prolong anesthesia. One approach that has heretofore been employed is to combine a vasoconstrictor agent such as epinephrine with a local anesthetic. However, this approach to increasing potency and/or duration of action is limited by the risk of causing tissue necrosis due to excessive localized vasoconstriction.
Another approach was based on analysis of the structure-activity relationship of the local anesthetic compounds. Structure-activity analysis for local anesthetic compounds indicates that relative increases in hydrophobicity are accompanied by relative increases in the potency and in duration of action of these agents. Unfortunately, relative increases in hydrophobicity also elevate the toxic tissue effects, therefore resulting in no effective improvement in the therapeutic index, i.e., no increase in safety will result from this approach. The most recent example of this approach is Naropin(trademark) (ropivacaine, Astra Pharmaceuticals), which was reported to be a safer (relative to bupivacaine solution) long acting amide local anesthetic for injection. However, one condition for the approval of ropivacaine is that the package insert warn against rapid injection in large doses, since it is expected to share the risk of cardiac arrhythmias, cardiac/circulatory arrests and death if inadvertently injected intravenously (F-D-C Reportsxe2x80x94xe2x80x9cThe Pink Sheetxe2x80x9d, Dec. 18, 1995). Thus, there remains a need in the art for methods and formulations enhancing the safety of administration of local anesthetics.
Different methods and formulations are known in the art for administration of local anesthetics. For example, U.S. Pat. Nos. 4,725,442 and 4,622,219 (Haynes) are directed to microdroplets of methoxyflurane-containing microdroplets coated with a phospholipid prepared by sonication, which are suitable for intradermal or intravenous injection into a patient for inducing local anesthesia. Such microdroplets are said to provide long-term local anesthesia when injected intradermally, giving a duration of anesthesia considerably longer than the longest acting conventional local anesthetic (bupivacaine).
WO 94/05265 describes improved biodegradable controlled release systems consisting of a polymeric matrix incorporating a local anesthetic for the prolonged administration of the local anesthetic agent. The devices are selected on the basis of their degradation profiles: release of the topical anesthetic in a linear, controlled manner over the period of preferably two weeks and degradation in vivo with a half-life of less than six months, more preferably two weeks, to avoid localized inflammation. The disclosure states that an anti-inflammatory can be incorporated into the polymer with the local anesthetic to reduce encapsulation for optimal access of drug to its site of action. The anti-inflammatories that are said to be useful include steroids such as dexamethasone, cortisone, prednisone, and others routinely administered orally or by injection.
However, methods have not previously been known to provide for safe, regulated administration of a local anesthetic resulting in greatly reduced toxicity and an enhanced therapeutic index to provide both short term and long term sensory and motor anesthesia to a local area of a patient in need of such treatment.
Accordingly, it is therefore an object of the present invention to provide compositions for providing safe local anesthesia with a substantially reduced risk of toxic reactions and/or untoward side effects.
It is a further object of the present invention to provide methods for providing a safe local anesthesia which effectively controls acute and chronic pain, including post-traumatic and post-operative pain.
In accordance with the above-mentioned objects and others, the invention is related to the discovery that controlled release local anesthetic formulations prepared, e.g., in the form of injectable microspheres, provide both immediate local anesthesia after administration, and provide greatly enhanced safety. Thus, the controlled release formulations according to the invention release enough local anesthetic, in vivo, to provide a normal onset of local anesthesia. However, in an unexpected benefit, the same controlled release local anesthetic formulations fail to cause the expected toxic results when injected into test animals in what would otherwise be toxic amounts. Thus, the present invention provides methods and compositions for inducing local anesthesia with a substantially reduced risk of untoward toxicity and undesirable effects.
The controlled release formulation can be formed into slabs, pellets, microparticles, microspheres, microcapsules, spheroids and pastes. Preferably, the formulation is in a form suitable for suspension in isotonic saline, physiological buffer or other solution acceptable for injection into a patient.
The invention further provides methods for inducing localized anesthesia by implanting, inserting or injecting a controlled release formulation, e.g., in the form of injectable microspheres loaded with a local anesthetic in sustained release form, into a site at or adjacent to a nerve or nerves innervating a body region to provide local anesthesia. Thus, the safe local anesthetic formulation according to the invention can be injected, infiltrated or implanted at a site in a patient where the local anesthetic agent is to be released. Optionally, the safe local anesthetic formulation can also be applied topically, e.g., to skin and/or mucosal surfaces.
Further aspects of the invention are directed to a method of treating a patient in need of a surgical procedure, comprising placing a safe local anesthetic form in proximity to a nerve or nerves at the surgical site.
Therefore, the present invention provides for safe regional local anesthesia at a site in a patient, by administering at the site a local anesthetic incorporated in a biocompatible, biodegradable, controlled release formulation where the site of administration is located at or adjacent to a nerve or nerves innervating a region of the patient to be so anesthetized. Further, the local anesthetic is present in a concentration effective to safely achieve sensory or motor local anesthesia with reduced toxicity, and the local anesthetic is released at a rate effective to safely achieve sensory or motor local anesthesia. In one aspect, the method of the invention provides for at least a portion of the local anesthetic in immediate release form.
In one preferred embodiment, the method provides for preparing the controlled release form as a plurality of microspheres, suspending the microspheres in a pharmaceutically acceptable medium for injection, and injecting said microspheres at a site in a patient, for example, in proximity to a nerve to be anesthetized. The local anesthetic can be incorporated into the formulation, such as, for example the plurality of controlled release microspheres at a percent loading of 0.1% to 90% and in a preferred embodiment, at a percent loading ranging from about 20% to about 80%, by weigh, and in a more preferred embodiment, at a percent loading ranging from about 70% to about 80%, by weight.
Although any pharmaceutically acceptable local anesthetic may be employed according to the method of the invention, the local anesthetic is preferably selected from bupivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine and xylocaine, and salts, derivatives or mixtures thereof. In a more preferred embodiment, the local anesthetic is bupivacaine. The method can be conducted with bupivacaine HCl, bupivacaine free base and/or mixtures thereof While the artisan will understand that the dose will vary according to the size and weight of the patient and the number of nerves to be blocked and/or treated, the bupivacaine is administered in a dose ranging from 5 through 450 mg/kg of a patient. Alternatively, bupivacaine is administered according to the invention in a dose ranging from about 0.5 mg to about 200 mg or more, depending upon the aforementioned factors. Preferably, bupivacaine is administered in a dose ranging from about 1 to about 50 mg or more, and more preferably, bupivacaine is administered in a dose ranging from about 1 to about 20 mg, depending upon the above listed factors. Of course, the artisan will appreciate that the dosage ranges of other art-known local anesthetics can be determined relative to the potency of bupivacaine.
The method of the invention may also be conducted by administering a formulation prepared as a unit dosage of the controlled release formulation comprising, in a container, a sufficient amount of the formulation to induce local anesthesia in at least one patient. In one embodiment, the unit dosages are sterile and lyophilized. Alternatively, the unit dosages are sterile and prepared as a suspension in a solution acceptable for injection into a patient.
The controlled release local anesthetic dosage form may be injected and/or infiltrated, at the site where the anesthetic is to be released. This can be prior to surgery, at the time of surgery, or following removal (discontinuation) or reversal of a systemic anesthetic.
According to the invention, an effective local anesthetic dose of the biocompatible, biodegradable, controlled release formulation according to the invention will, when injected into the patient intravenously, fail to induce a toxic reaction or alternatively, be much less likely to induce a toxic reaction relative to the toxicity of bupivacaine HCl or bupivacaine free base. In another aspect, when the local anesthetic is bupivacaine an intravenously administered dose, measured by the amount required to produce an effective local anesthesia, of the biocompatible, biodegradable, controlled release formulation will be unable to produce a bupivacaine blood plasma level of about 1600 ng/ml or, alternatively, no more than about 1200 ng/ml of plasma bupivacaine. In a further aspect, when the local anesthetic is bupivacaine, an intravenously administered dose, measured by the amount required to produce an effective local anesthesia, of the biocompatible, biodegradable, controlled release formulation will be unable to produce a bupivacaine blood plasma higher than from about 200 to about 650 ng/ml.
Examples demonstrate the greatly enhanced safety and greatly reduced toxicity provided by the methods and formulations according to the invention.